1, 2, 3, 4-tetrahydro-1, 4-methano-naphthalene-2, 3-dicarboximides



United States Patent M 3,210,374 1,2,3,4-TETRAHYDRO-1,4-METHANO-NAPH'IHA- LENE-2,3-DlICARllOXlMEDES Charles Ferdinand Huebner, Chatham, NJ, assignor to Ciba Corporation, New York, N.Y., a corporation of Delaware N0 Drawing. Filed May 9, 1963, Ser. No. 279,307 ll tElaims. (Cl. 260-3265) This is a continuation-in-part application of my application Serial No. 209,748, filed July 13, 1962, which is now abandoned.

The present invention concerns dicarboximide compounds. More particularly it relates to 1,2,3,4-tetrahydro- 1,4-methano-naphthalene 2,3-dicarboximides unsubstituted at the l-oosition, the 2-position, the 4-position and the methane carbon atom. These compounds may be further substituted; for example, they may contain an aliphatic radical, above all, lower alkyl, at the imido-nitrogen atom. They may also be substituted at the hexacyclic carbocyclic aryl portion of the 1,2,3,4-tetrahydro-l,4- methano-naphthalene nucleus as outlined below; furthermore, they may have a substituent at the 2-position, advantageously lower alkyl, or salts of those compounds having a salt-forming substituent, as well as process for the preparation of such compounds.

The compounds of this invention are especially those of the following formula:

in which Ph stands for a 1,2-phenylene radical, R is hydrogen or an aliphatic radical, and R is hydrogen or lower alkyl, and salts of those compounds having a saltforming substituent, as well as process for the preparation of such compounds.

The 1,2-phenylene radical (also o-phenylene radical), representing the hexacyclic carbocyclic aryl portion of the l,2,3,4-tetrahydro-l,4methano-naphthalene nucleus is preferably unsubstituted 1,2-phenylene. It may be a substituted 1,2-phenylene radical which contains one or more than one of the same or of diflerent substituents attached many of four positions available for substitution. Substituents are, for example, lower alkyl, e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl and the like, hydroxyl, etherified hydroxyl, especially lower alkoxy, e.g., methoxy, ethoxy and the like, as well as lower alkenyloxy, e.g., allyloxy and the like, or lower alkylenedioxy, e.g., methylenedioxy and the like, esterified hydroxyl, particularly halogeno, e.g., fiuoro, chloro, bromo and the like, trifluoromethyl, nitro, amino, such as N-unsubstituted amino, N-mono-substituted amino, for example, N-lower' alkyl-amino, e.g., N-methylamino, N-ethylamino and the like, or N,N-disubstituted amino, for example, N,N-dilower alkyl-amino, e.g., N,N-dimethylamino, N,N-diethylamino and the like, etherified mercapto, such as lower alkyl-mercapto, e.g., methylmercapto, ethylmercapto and the like, or any other suitable substituent. 1,2- phenylene radicals representing the hexacyclic carbocyclic aryl portion of the 1,2,3,4-tetrahydro-l,4-methano-naphthalene nucleus of the compounds of this invention, i.e., the group Ph, are above all 1,2-phenylene, but may also be (lower alkyl)-1,2-p-henylene, (hydroxy) ll-phenylene, (lower a-lkoxy)-l,2-phenylene, (lower alkenyloxy)-1,2- phenylene, (lower alkylenedioxy)-l,2-phenylene, (halogeno) 1,2-phenylene, (triiluoromethyl) 1,2-phenylene, (nitro)-1,2-phenylene, (amino)-l,2-phenylene, (N-lower alkyl-amino)-l,2-phenylene, (N,N-di-lower alkyl-amino)- 3,216,374 Patented Get. 5, 1965 1,2-phenylene, (lower alkyl-mercapto)-l,2-phenylene and the like.

The imido-nitrogen may be unsubstituted or substituted by an aliphatic radical. In the above formula, the group R attached to the imido-nitrogen is hydrogen or may be an aliphatic radical, such as an aliphatic hydrocarbon radical or a substituted aliphatic hydrocarbon radical. An aliphatic hydrocarbon radical is about all lower alkyl, especially methyl, as well as ethyl, n-propyl, isopropyl, nbutyl, isobutyl, secondary butyl and the like, but may also be lower alkeny'l, e.g., allyl, Z-methylallyl, Z-butenyl and the like, lower alkynyl, e.g., propa-rgyl, Z-butynyl and the like, as well as a cycloaliphatic hydrocarbon radical such as cycloalkyl having from three to eight, particularly from five to seven, ring carbon atoms, e.g., cyclopropyl, cyclopentyl, cycloheptyl and the like, cycloalkenyl having from five to eight, especially from five to seven, ring carbon atoms, e.g., 2-cyclopentenyl, 3-cyclohexenyl and the like. A substituted aliphatic hydrocarbon radical is, for example, a cycloaliphatic-aliphatic radical, such as cycloalkyl-lower alkyl, in which cycloalkyl has from three to eight, especially from five to seven, ring carbon atoms, e.g., cyclopentylmethyl, l-cyclopentylethyl, cyclohexylmethyl, Z-cyclo-hexylethyl and the like, or cycloalkenyllower alkyl, in which cycloalkenyl has from five to eight, especially from five toseven, ring carbon atoms, e.g., 2- cyclopentenylmethyl, 1-(1-cyclopentenyl)- ethyl, 3-cyclohexenylmethyl, 2-(3-cyclohexenyl) -ethyl and the like, or a carbocyclic arylaliphatic radical, such as monocyclic ca-rbocyclic aryl-lower alkyl, particularly phenyl-lower alkyl, e.g., benzyl, l-phenylethyl, 2-phen ylethyl and the like.

The carbon atom representing the 2-position may be unsubstituted or substituted, particularly by lower alkyl. The group R attached to the 2-position of the compounds of the above formula stands primarily for hydrogen, but may also be lower alkyl, particularly methyl, as well as ethyl, n-propyl, isopropyl, n-butyl and the like, It may have the (it-configuration or the 8-configuration Salts of the compounds having a salt-forming group, e.g., an amino group, are acid addition salts, particularly pharmaceutically acceptable, non-toxic acid addition salts, with inorganic acids, e.g., hydrochloric, hydrobr-omic, sulfuric, phosphoric acids and the like, or with organic acids, such as organic carboxylic acids, e.g., acetic, succinic, maleic, tartaric, citric acid and the like, or organic sulfonic acids, e.g., methane sulfonic, Z-hydroxy-sulfonic, p-toluene sult'onic, naphthalene 2-sulfonic acid and the like. Acid addition salts may also be used as intermediates, for example, in the preparation of other acid addition salts, such as pharmaceutically acceptable, nontoxic acid addition salts, or in the purification of the free compounds, or may serve for identification or characterization purposes. Salts for the latter are, for example, those with acidic nitro compounds, e.g., picric, picrolonic, flavianic acid and the like, or with metal complex acids, e.g., phosp'hotungstic, phosphomolybdtic, chloroplatinic, Reinecke acid and the like.

The compounds of the present invention have hypnotic and sedative effects. They are characterized by a fast onset of the hypnotic and sedative effects, and do not exhibit the prehypnotic excitation often associated with hypnotic compounds; furthermore, the pharmacological elfects are of prolonged duration. Compounds of this invention, in which the group R in the above formula is lower alkyl, especially methyl, are more predominantly sedative and show less pronounced hypnotic effects. Compounds of the present invention also have skeletal muscle relaxant effects or anticonvulsive properties.

The compounds of this invention are primarily used as improved night-time hypnotic agents in cases of chronic or acute insomnia, or as hypnotic agents prior to anesthesia in major surgery. Furthermore, compounds, in which R in the above formula is lower alkyl, especially methyl, can also be used as daytime sedatives in conditions :of overactiveness, nervousness, aniexty and the like. Compounds of this invention having skeletal musclerelaxant or anticonvulsive effects may be used as muscle relaxants, for example, during general anesthesia in surgery or to overcome abnormal muscle spasms, or to relieve epileptic seizures of the petit or grand mal type. The compounds may also serve as intermediates for the preparation of other useful compounds.

The compounds of this invention are especially those of the formula in which R is hydrogen or lower alkyl, especially methyl, R is primarily hydrogen, but may also be lower alkyl, particularly methyl, and R is primarily hydrogen, but may also stand for lower al-kyl, halogeno, trifluoromethyl, nitro or amino, and acid addition salts of those compounds having an amino group as a salt-forming substituent. The compounds having one of the formulae represent a preferred group of compounds having the above-described hypnotic properties. Above all, the endol,'2,3,4 tetrahydro-1,4-methano-naphthalene boximide of the formula in which Ph and R have the previously given meaning,

2,3-dicar- 0 4- or preferably a reactive functional acid derivative of such dicarboxylic acid, into a l,2,3,4-tetrahydro-1,4-methanonapththalene 2,3-dicarboximide compound unsubstituted at the l-position, the 3-position, the 4-position and the methano carbon atom, particularly into the compound of the formula in which Ph, R and R have the previously given meaning and, if desired, replacing in a resulting dicarboximide compound having a hydrogen atom at the imido-nitrogen, i.e., in a compound of the above formula, in which R is hydrogen, such hydrogen by an aliphatic radical, and/or, if desired, introducing into the hexacyclic carbocyclic aryl portion of the 1,2,3,4-tetrahydro-1,4-methano-naphthalene nucleus, i.e. the 1,2-phenylene portion, of a resulting compound a substituent, and/or, if desired, converting a substituent of the hexacyclic carbocyclic aryl portion of the l,2,3,4-tetrahydro-1,4-methano-naphthalene nucleus, i.e., the 1,2-phenylene portion, of a resulting compound into another substituent, and/or, if desired, converting a resulting compound having a salt-forming group into a salt thereof.

The above conversion reaction is preferably carried out by using as the starting material a reactive functional acid derivative of the dicarboxylic acid. Especially useful as starting materials are the acid anhydrides; other suitable reactive functional acid derivatives of the dicarboxylic acid starting materials are anhydrides with other acids (i.e., mixed anhydrides), esters, halides or nitrogen-containing derivatives, such as the ammonium salts, the amides, the nitriles and the like. Furthermore, mixed functional derivatives of the dicarboxylic acid may also serve as starting materials, such as the acid-monoanhydrides, acid-monoamides, the ammonium salts of the monoamides, the ester-amides, the ester-nitriles and the like.

The conversion of the dicarboxylic acid starting materials or the functional derivatives thereof into the desired dicarboximide compounds of this invention is carried out according to known methods. In the course of the reaction, the dicarboxylic acid starting materials or functional acid derivatives thereof may yield intermediate compounds, which, under the conditions of the reaction or upon further treatment, are then converted into the desired dicarboximide compounds.

As mentioned above, the anhydrides of the dicarboxylic acid starting materials are the preferred functional acid derivatives thereof. Such acid anhydride may be converted into an N-unsubstituted dicarboximide by treating it with ammonia or an ammonia-furnishing reagent. Such reaction may first lead to the formation of a dicarboxylic acid monoamide intermediate or a functional derivative thereof. Thus, the reaction of the anhydride with ammonia (for example, a concentrated aqueous solution thereof) may yield first the ammonium salt of the dicarboxylic acid monoamide, which upon heating (for example, during concentration of the reaction mixture at an elevated temperature) is converted into the desired dicarboximide. Other reagents used for the formation of the desired dicarboximides from the dicarboxylic acid anhydride starting materials are, for example, ammoniafurnishing ammonium salts, particularly those of lower alkanoic acids, e.g., ammonium acetate and the like, which are preferably used in the presence of the corresponding acid, e.g. acetic acid and the like, and at an elevated temperature to ensure completon of the reaction. Formamide is another reagent suitable for the conversion of an anhydride into the desired dicarboximide compound; it is preferably used at an elevated temperature and without the presence of an additional diluent.

Reagents furnishing the imido-nitrogen substituted dicarboximide compounds from the anhydride starting materials are N-monosubstituted amines, such as N-aliphatic monosubstituted amines, especially the N-lower alkylamines, e.g., N-methylamine, N-ethyl-amine and the like, or salts of such amines. Again, these reagents may yield as intermediates nitrogen-containing derivatives of the cis-dicarboxylic acids, primarily monoamides thereof or functional derivatives of such monoamides; upon internal acylation (brought about, for example, by heating), these intermediates are converted into desired dicarboximides. Whenever used in the free form, these amines may be added, for example, to a mixture of the dicarboxylic acid anhydride and acetic acid containing an alkali, e.g., sodium, potassium and the like, metal acetate; heating may be necessary to complete the internal cyclization. Salts of the N-monosubstituted amines are acid addition salts thereof, particularly the mineral acid addition salts thereof, e.g., hydrochlorides, hydrobromides, sulfates and the like; they may also be employed, preferably in the presence of acetic acid and an alkali metal, e.g., sodium potassium and the like, acetate, and while heating. Other reagents useful for the formation of N-substituted dicarboximides, are, for example, N-lower alkyl-formamides, e.g., N-methyl-formamide and the like; treatment of a dicarboxylic acid anhydride with such a reagent is carried out at an elevated temperature.

Anhydrides with other acids, i.e., mixed anhydrides, are converted into the desired dicarboximides according to the above procedure, preferably after intramolecular acylation of an intermediate amide compound.

Other functional acid derivatives of the l,2,3,4-tetrahydro-l,4-methano-naphthalene 2,3-cis-dicarboxylic acid starting materials, such as, for example, the half-esters, or more especially the diesters, particularly the esters with lower alkanols, e.g., methanol, ethanol and the like, or any other suitable alcoholic hydroxyl-compounds, are converted into the desired l,2,3,4-tetrahydro-l,4-methanonaphthalene 2,3-dicarboximides according to the previously described procedure, i.e., by treatment with ammonia or an ammonia-furnishing reagent, or with a monosubstituted amine, if necessary, with subsequent intrarnolecular acylation.

Further functional acid derivatives of the dicarboxylic acid starting materials, such as the ii-halides, particularly dichlorides and the like, or the monoester monohalides, e.g., a mono-lower alkyl-ester chloride and the like, of a 1,2,3,4-tetrahydro-l,4-methano-naphthalene 2,3-cis-dic-arboxylic acid, when treated with ammonia or one of the above amines, yield the desired dicarboximide compounds.

l'-litrogen-containing derivatives of the l,2,3,4-tetrahydro-1,trnetlrano-naphthalene 2,3-cis-dicarboxylic acid starting materials, such as the cis-dicarboxylic acid monoamides or functional derivatives thereof, which, as has been shown above, may be formed as intermediates in the treatment of a dicarboxylic acid anhydride with the various ammoni and amine-furnishing reagents, may generally be used as functional derivatives of dicarboxylic acids serving as starting materials in the above procedure. Other nitrogen-containing functional derivatives of the cis-dicarboxylic acid starting materials, such as the mononitriles, the dinitriles, the nitrile-esters (for example, nitrile lower alkyl esters, e.g., nitril-e ethyl esters, etc.) and the like, thereof may also be used as starting materials. Upon treatment with a condensing reagent, for example, a strong Lewis acid, such as a strong mineral acid, e.g., sulfuric, phosphoric acid (preferably in the form of polyphosphoric acid) and the like, a mixture of acids, e.g., sulfuric acid and acetic acid and the like, an acid anhydride, e.g., acetic acid anhydride and the like, condensing reagents used in the Friedel-Crafts reaction, e.g., aluminum chloride, stannie chloride, zinc chloride and the like, boron trifiuoride (in the form of its etherate) or any other suitable Lewis acid condensing reagent, either in the absence or in the presence of a diluent, these starting materials may be converted into the desired 1,23,4- tetrahydro-1,4-methano-naphthalene 2,3-dicarb oximides. This reaction may also lead to the formation of the intermediarily formed 2,3-cis-dicarboxylic acid Inonoamides or functional derivatives thereof; upon internal acylation, for example, by heating, these intermediates are converted to the desired dicarboximides.

The diamides, the di-ammonium salts or the mononitrile ammonium salts of the cis-dicarboxylic acids, may also be used as starting materials; upon intramolecular condensation, which may be brought about, for example, by heating, these compounds are converted into the desired dicarboximide compounds.

The above-mentioned starting materials are known, or, if new, may be prepared according to known methods used for the preparation of analogous compounds. Thus, the anhydrides may be prepared by reacting an indene compound with a maleic acid anhydride according to the Diels-Alder reaction, and from a resulting endo-l,2,3,4- tetrahydro-l,4-methano-naphthalene 2,3-dicarboxylic acid anhydride, esters of the 2,3'cis-dicarboxylic acid may be prepared by alcoholysis and the free 2,3-cis-dicarboxylic acid by hydrolysis. From a free 2,3-cis-dicarboxylic acid compound, or a monoester thereof, the ammonium salt may be formed, which may be dehydrated to yield the amide (which may also be obtained from the ester by reaction with ammonia or an amine) and/ or the nitrile. These reactions are carried out according to known procedures and methods. The cndo-form resulting from the above Diels-Alder reaction may be converted into the exoform, for example, by treatment of the endo-form of a 2,3-cis-dicarboxylic acid ester with a base, such as an alkali metal hydroxide, whereupon the exo-form of the corresponding 2,3-cisdicarboxylic acid can be isolated.

Compounds resulting from the above procedure may be converted into other compounds. Thus, in a resulting compound having an imido-nitrogen with a hydrogen atom, such hydrogen may be replaced by an aliphatic radical, such as, for example, an aliphatic hydrocarbon radical or a substituted aliphatic hydrocarbon radical, particularly by lower alkyl. This may be achieved, for example, by reacting the N-unsubstituted dicarboximide compound or preferably a metal salt, such as an alkali metal, e.g., lithium, sodium, potassium and the like, salt thereof with a reagent capable of introducing an aliphatic radical. The metal salt (which may be prepared, for example, by treating the N-unsubstituted dicarboximide compound with an alkali metal, e.g., lithium, sodium, potassium and the like, as well as an amide, a hydride, a hydrocarbon compound, a lower alkanolate of such a metal, e.g., sodium amide, sodium hydride, butyl lithium,

phenyl lithium, potassium tertiary butylate, potassium tertiary a-mylate and the like) is preferably treated with a reactive ester of an aliphatic alcohol such as a lower alkanol and the like. Reactive esters of alcohols, especially lower alkanols, are those with strong inorganic or organic acids, such as mineral acids, e.g., hydrochloric, hydrobromic, sulfuric acid and the like, or organic sulfonic acids, e.g., p-toluene sulfonic acid and the like. These reagents are represented, for example, by the lower alkyl halides e.g., methyl, ethyl, n-propyl or isopropyl chloride, bromide or iodide and the like, the di-lower alkyl sulfates, e.g., dimethyl sulfate, diethyl sulfate and the like, the lower alkyl esters of organic: sulfonic acids, such as lower alkyl p-toluene sulfonates, e.g., methyl ptoluene sulfonate and the like. Other suitable reagents for replacing the hydrogen atom in a resulting N-unsubstituted dicarboximide compound of this invention, are diam-compounds, such as lower diazo-alkanes, e.g., diazomethane, diazoethane and the like.

Furthermore, substituents may be introduced into the hexacyclic carbocyclic aryl portion, i.e., the 1,2-phenylene portion, of a resulting compound. For example, upon treatment with a nitrating reagent, e.g., a mixture of nitric acid and acetic acid anhydride, sulfuric and nitric acid and the like, a nitro group may be introduced; resulting mixtures of nitrated compounds may be separated, for example, on the basis of solubility differences.

In addition, a substituent attached to the hexacyclic carbocyclic aryl portion, i.e., the 1,2-phenylene portion, of a resulting compound may be converted into another substituent. For example, a nitro group may be converted into a N-unsubstituted amino group, for example, by treatment with hydrogen in the presence of a catalyst containing a metal of the eighth group of the Periodic System e.g., Raney nickel, platinum oxide and the like, or into an N-substituted amino group, such as an N-lower alkylamino group, e.g., N-methylamino and the like, or N,N-di-lower alkyl-amino, e.g., N,N-dimethylamino and the like, for example, by carrying out the above reduction in the presence of an aldehyde or a ketone, e.g., formaldehyde. In addition, an N-unsubstituted amino group may be replaced by halogeno, e.g., chloro, bromo and the like; for example, a resulting dicarboximide compound having an amino group attached to the hexacyclic carbocyclic aryl portion may be treated with nitrous acid and converted into a diazo compound, which is then reacted Wtih a cuprous halide, e.g., cuprous chloride, cuprous bromide and the like, according to the Sandmeyer proce dure. Furthermore, an etherified hydroxyl group, such as lower alkoxy, attached to the hexacyclic carbocyclic aryl portion of a resulting compound may be converted into a hydroxyl group by acid hydrolysis, for example, with hydrobromic acid, 'hydriodic acid, aluminum chloride and the like, or any other suitable reagent.

A resulting compound having a salt-forming group, particularly a compound having a basic group, such as an amino group, may be converted into a salt, particularly into an acid addition salt thereof, according to known methods, for example, by reacting it with a suitable acid, preferably in the presence of a diluent or a mixture of solvents.

The invention also comprises any modification of the process wherein a compound obtainable as an intermediate at any stage of the process is used as starting material and the remaining step(s) of the process is (are) carried out, as well as any new intermediates.

In the process of this invention such starting materials are preferably used which lead to final products mentioned in the beginning as preferred embodiments of the invention.

The following examples are intended to illustrate the invention and are not to be construed as being limitations thereon. Temperatures are given in degrees Centigrade.

Example 1 A mixture of 20.0 g. of endo-1,2,3,4-tetrahydro-1,4- rnethano-naphthalene 2,3-dicarboxylic acid anhydride, and 20.0 g. of ammonium acetate in 200 ml. of glacial acetic acid is refluxed for 5 /2 hours. The acetic acid is then distilled off under reduced pressure and the residue is poured into water. The endo-1,2,3,4-tetrahydro-1,4- methano-naphthalene 2,3-dicarboximide of the formula precipitates and is recrystallized from ethanol, M.P. 232 233; yield: 15 g.

The starting material is prepared as follows: A mixture of 200 g. of indene and 120 g. maleic acid anhydride in 200 ml. of benzene in a stainless steel bomb is heated to 250 for five hours. After cooling to 3035, the super- 8 natent solvent is decanted from the polymeric residue. A mixture of a polymeric substance and the desired endo- 1,2,3,4 tetrahydro 1,4 methanonaphthalene 2,3-dicarboxylic acid anhydride separates from the benzene solution; the latter is obtained in pure form by recrystallization from ethyl acetate, M.P. -182".

Example 2 To a solution of 10.0 g. of endo-1,2,3,4-tetrahydro- 1,4-methano-naphthalene 2,3-dicarboxylic acid anhydride in 60 ml. of glacial acetic acid is added 6.32 g. of N methyl-amine hydrochloride and 7.75 g. of sodium acetate. The reaction mixture is refluxed over night; the acetic acid is then evaporated under reduced pressure. The residue is diluted with water and the crystalline endol2,3,4-tetrahydro-1,4 methane naphthalene N-methyl- 2,3-dicarboximide of the formula rt 11 o e l l e m N-crr 1 1 ir c") is filtered off, washed with water, air-dried and recrystallized from ethanol, M.P. 146-148"; yield: 8.5 g.

Example 3 A mixture of 0.85 g. of exo 1,2,3,4 tetrahydro 1,4- methano-naphthalene 2,3-dicarboxylic acid anhydride in 10 ml. of glacial acetic acid is refluxed for 5 /2 hours in the presence of 1.0 g. of ammonium acetate. The acetic acid is evaporated under reduced pressure and water is added to the residue; the precipitate is filtered off, washed with water and air-dried. The desired exo-1,2,3,4-tetrahydro-1,4-metl1ane-naphthalene 2,3-dicarboximide of the formula is purified by crystallization from ethanol, M.P. 188-190"; yield: 0.4 g.

The starting material used in the above procedure is prepared as follows: A mixture of 16.0 g. of end0-1,2,3,4- tetrahydro-1,4-methano-naphthalene 2,3-dicarboxylic acid anhydride and 16 ml. of concentrated sulfuric acid in 200 ml. of methanol is refluxed for four hours, and is then diluted with a large volume of water. The organic material is extracted with diethyl ether; the organic phase is separated, washed with water, dried over calcium chloride and evaporated to yield the oily dimethyl endo-1,2,3,4- tetrahydro-1,4-methano-naphthalene 2,3 cis dicarboxylate, which crystallizes from methanol, M.P. 7l76; yield 12.73 g.

A mixture of 5.0 -g. of dimethyl endo-1,2,3,4-tetrahydro-1,4-methanol-naphthalene 2,3-cis-dicarboxylate in 63 ml. of methanol containing 5.0 g, of sodium is refluxed for five hours. After being diluted with 10 ml. of water, the reaction mixture is again refluxed for one hour and is then cooled and diluted with water. The organic material is extracted with diethyl ether; the organic solution is allowed to stand, whereupon the desired exo-1,2,3,4- tetrahydro-1,4-methano-naphthalene 2,3-cis-dicar-boxylic acid precipitates. After standing for several hours, it is filtered off and recrystallized from acetonitrile, M.P. 233436.

A total of 1.8 g. of exo-1,2,3,4-tetrahydro-l,4methanonaphthalene 2,3-cis-dicarboxylic acid is heated at a temperature above 300 for thirty minutes to yield 1.0 g. of

the exo-1,2,3,4-tetrahydro-1,4-methano-naphthalene 2,3- dicarboxylic acid anhydride.

Example 4 1? CH3 it llH NH ELL fr 1 ii is collected and recrystallized from ethanol, MP. 198- 200"; yield: 2.0 g.

The starting material used in the above procedure is prepared as follows: A mixture of 22.3 g. of citraconic acid anhydride, 31.3 ml. of indene and 0.1 g. of hydroquinone in 50 ml. of benzene is placed into the glassliner of an autoclave and heated at 250 for five hours. The precipitate is filtered off and recrystallized from ethyl acetate to yield the endo-Z-methyl-1,2,3,4-tetrahydro-1,4- methano naphthalene 2,3 dicarboxylic acid anhydride, M.P. 193-196; yield: 11.0 g.

Example 5 A mixture of 3.0 g. of endo-Z-methyl-1,2,3,4-tetrahydro-l,4-methano-naphthalene 2,3-dicarboxylic acid anhydride, 1.78 g. of N-methylamine hydrochloride and 2.17 g. of sodium acetate in 30 ml. of glacial acetic acid is refluxed for fifteen hours. The solvent is removed by distillation under reduced pressure and the residue is taken up into water. The precipitate is filtered off and recrystallized from ethanol to yield the endo-2-methy1-1,2,3,4- tetrahydro-1,4 methano naphthalene N methyl-2,3-dicarboximide of the formula which melts at 146-147; yield: 2.1 g.

Example 6 A mixture of ml. of fuming nitric acid and 85 ml. of

acetic acid anhydride is cooled to 0, and 9.5 g. of endois air-dried (yield: 8.2 g.) and recrystallized from acetone, MP. 240243 Example 7 A solution of 2.0 g. of endo-6-nitro-1,2,3,4-tetrahydro- 1,4-methano-naphthalene 2, 3-dicarboximide in ethyl acetate is treated with hydrogen under a pressure of about 3 atmospheres and in the presence of 0.15 g. platinum oxide as the catalyst; the hydrogenation reaction is carried out in a Parr hydrogenation apparatus while shaking, and the theoretical amount of hydrogen is absorbed after three hours. The catalyst is filtered off, the filtrate is evaporated to dryness under reduced pressure, and the crude endo6-arnino-1,2,3,4-tetrahydro 1,4 methano-naphthalene 2,3-dicarboximide of the formula is recrystallized from a mixture of methanol and diethyl ether, MP. 235237.

The endo 6 amino-1,2,3,4-tetrahydro-1,4-methanonaphthalene 2,3-dicarboximide maleate and the endo-6- amino1,2,3,4-tetrahydro 1,4 methano-naphthalene 2,3- dicarboximide picrate are prepared by adding maleic acid and picric acid, respectively, to a solution of the endo-6- amino-1,2,3 ,4-tetrahydro-1,4-methano-naphthalene 2,3-dicarboximide.

Other compounds, which may be prepared according to the above procedure by selecting the appropirate starting materials are, for example, endo'l,2,3,4-tetrahydro-1,4- methano-naphthalene N-ethyl-2,3-dicarboximide, endo- 1,2,3 -4-tetrahydro-1,4-methano-naphthalene N-isopropyl- 2,3 -dicarb oximide, endo-6-methyl-1,2,3 ,4-tetrahydro-1,4- methano-naphthalene 2,3-dicarboximide, endo-6-chloro- 1,2,3,4-tetrahydro 1,4 methane-naphthalene 2,3-dicarboximide, exo6-chloro-1,2,3,4-tetrahydro-1,4 methanonaphthalene 2,3 dicarboximide, endo 6,7-dimethoxy- 1,2,3,4-tetrahydro-1,4-methano-naphthalene 2,3-dicarboximide, endo5-trifiuoromethyl-1,2,3,4-tetrahydro-1,4metharm-naphthalene 2,3 -dicarboximide, endo-5,8-dichloro- 1,2,3 ,4-tetrahydro-1,4-methano-naphthalene 2,3 -dicarboximide, endo'6-chloro-1,2,3,4 tetrahydro 1,4-methanonaphthalene N-methyl-2,3-dicarboximide, exo-6-nitro- 1,2,3 ,4-tetrahydro-l ,4-methano-naphthalen-e 2,3-dicarboximide, exo-6-amino-1,2,3,4-tetrahydro-1,4-methano-naphthalene 2,3dicarboximide, and the like; the latter may be converted into its hydrochloride by treatment with hydrogen chloride.

Also included within the scope of this invention are new pharmaceutical compositions consisting essentially of a pharmacologically effective amount of a 1,2,3,4-tetrahydro-l,4-methano-naphthalene 2,3-dicarboximide unsubstituted at the 1-position, the 3-position, the 4-position and the methano carbon atom, or a salt of such compound having a salt-forming substituent, such as a compound of the formula in which Ph, R and R have the previously given meaning, or a salt of such compound having a salt-forming substituent, especially a compound of the formula in which R R and R have the previously given meaning, or an acid addition salt of such compound having an amino group as a salt-forming substituent, as the active ingredient, together with a carrier, as well as a method for inducing sleep using the above compositions.

Preferred compositions are those which consist essentially of an effective amount of a compound having one of the formulae primarily the endo-l,2,3,4-tetrahydro-1,4-methano-naphthalene 2,3-dicarboximide as the pharmacologically active ingredient, together with an inert carrier.

The compositions are prepared by combining the active ingredient with a pharmaceuticaliy acceptable organic or inorganic carrier in specified proportions. The compositions of this invention may be made up to have from about percent to about 90 percent, preferably from about 25 percent to about 90 percent, by weight, of the pharmacologically active ingredient.

Tablets, capsules, dragees and the like represent the preferred oral form of administration. These orally applicable compositions may be compounded to have per single dosage unit from about 0.1 g. to about 0.75 g., especially from about 0.2 g. to about 0.5 g., of the active ingredient.

Apart from the active compound, the orally applicable preparations may contain substances commonly employed in the pharmaceutical art of preparing dosage unit compositions. These may include excipients, binders, fillers, stabilizers or any other suitable ingredients. Examples of such carrier materials are starch e.g., corn starch, wheat starch and the like, sugars, e.g., lactose, sucrose and the like, stearic acid, magnesium stearate, sodium lauryl sulfate, aluminum magnesium silicate preparations, talcum, tragacanth, acacia, gelatin, polyethylene glycol and the like. The quantities of these ingredients may vary widely and depend, to a certain degree, upon the desired physical appearance (softness and the like) and size 'of the composition, the manufacturing procedure thereof and the like. Encapsulation may also be effected using, if desired, the same excipients as those used for tablets. The compounding of the formulations is generally carried out in the manner normally employed in the art. Any compatible color, approved and certified under the provisions of the Federal Food, Drug and Cosmetic Law may be used as a means of identification or for aesthetic purposes.

Certain orally applicable compositions may also provide for a prolonged and sustained hypnotic effect. For example, tablets, such as those described in US. Patent 2,887,438, may contain the active ingredient embedded in a waxy core (for prolonged absorption in the lower intestine), around which is compressed a granulated mixture of the active ingredient together with a carrier (for immediate absorption in the stomach). Capsules for maintaining prolonged effects may contain, for example, micropills which have small particles of the active ingredient covered with coats having different rate-s of degradation. These longacting preparations are prepared according to known methods.

Example 8 Capsules each containing 0.25 g. of endo-1,2,3,4-tetrahydro-1,4-methano-naphthalene 2,3-dicarboximide are repared as follows (for 10,000 capsules):

Ingredients: G.

Endo-1,2,3,4-tetrahydro-1,4-methano-naphthalene 2,3-dicarboximide 2,500.00

Corn starch 120.80

Sodium lauryl sulfate 11.20

Talcum USP 84.00

Magnesium stearate 84.00

The sodium lauryl sulfate, the talcum and the magnesium stearate are blended in a suitable mixer; the corn starch is then added and mixing is continued. Finally, the endo- 1,2,3,4-tetrahydro-1,4-methano-naphthalene 2,3-dicarboximide is given to and is thoroughly blended with the mixture. Portions of 0.28 g. of the resulting product are filled into No. 1 hard gelatine capsules.

Example 9 Tablets each containing 0.25 g. of endo-1,2,3,4-tetrahydro-1,4-methano-naphthalene 2,3-dicarboximide are prepared as follows:

Ingredients: G.

Endo 1,2,3,4 tetrahydro-l,4-methanonaphthalene 2,3-dicarboximide 2,500.00 Gelatin 50.00 Wheat starch (12 percent moisture) 1,171.60 Magnesium stearate 34.00 Talcum (powdered) 135.00

Water, q.s *Dried 1031.00 g.

The endo-1,2,3,4-tetrahydro 1,4 methane-naphthalene 2,3-dicarboximide and 869 g. of the wheat starch are mixed. The gelatine is dissolved in 250 ml. of water While gently heating, and the balance of the wheat starch is suspended in 500 ml. of water. The gelatine solution and the wheat starch suspension are combined; upon heating on the Water bath, a paste is formed, which is then used to granulate the above mixture of the powders. The granulate is passed through a No. 8 screen, dried completely, passed through a No. 12 screen and mixed with the magnesium stearate and the talcum. The resulting product is compressed into tablets weighing 0.375 g. each by using inch standard concave punches.

In the above compositions the endo-l,2,3,4tetrahydro- 1,4-methano-naphthalene 2,3-dicarboximide may be replaced by other l,2,3,4-tetrahydro-1,4-methano-naphthalene 2,3-dicarboximide compounds, such as for example, exo-1,2,3,4-tetrahydro-1,4-methano-naphthalene 2,3-dicarboximide, endo-1,2,3,4-tetrahydro-1,4 methano-naphthalene N-rnethyl-2,3-dicarb0ximide, endo-2-methyl-1,2,3,4- tetrahydro-1,4-methano-naphthalene 2,3 dicarboximide, endo-2-methyl-1,2,3,4-tetrahydro-1,4 methano-naphthalene N-methyl-Z,3-dicarboximide, endo-6-amino 1,2,13,4- tetrahydro-1,4-methano-naphthalene 2,3 dicarboximide and the like.

What is claimed is:

1. A member of the group consisting of a compound of the formula in which Ph stands for a member selected from the group consisting of 1,2-phenylene, (lower alkyl)-l,2-phenylene, methano'naphthalene (hydroxy)-1,2-phenylene, (lower alkoXy)-1,2-phenylene, z3'dlcarboxlmlde (lower alkenyloxy) 1,2 phenylene, (lower alkylenedi- EXOT1.234'tetrahydm'l4'methanonaphthalene oxy) 1,2-phenylene, (halogeno) 1,2-phenylene, (tridlcarboxlmlde' fluoromethyl) 1,2-phenylene, (nitro)1,2 phenylene, 6'Acompound ofthe formula (amino) 1,2-phenylene, (N-lower alkyl-amino) 1,2- phenylene, (N,N-di-lower alkyl-amino) 1,2-phenylene, and (lower alkyl-mercapto)-1,2-phenylene, R is a mernber selected from the group consisting of hydrogen, lower l N-CH alkyl, lower alkenyl, lower alkynyl, cycloalkyl having 3 from three to eight ring carbon atoms, cycloalkenyl having from five to eight ring carbon atoms, cycloalkyl-lower ll alkyl, in which cycloalkyl has from three to eight ring carbon atoms, and cycloalkenyl-lower alkyl, in which Endo1,f2,34'teFr{hYdr'1,4-methanQ-naphtha1ene cyeloalkenyl has from five to eight ring carbon atoms, methylz3'dlcarboxlmldeand R is a member selected from the group consisting of tetrahydmqri methano' hydrogen and lower alkyl, and an acid addition salt therenaphthalene zl3'dlcarboxlmldeof, wherein Ph is a member selected from the group con- Endoz'methyl'l,z3:4jtetrahyfhcf 7 methanosisting of (amino)1,2-pheny1ene, (N-lower alkyl-amino)- naphthalene 'm Y 1,2 phenylene and (NNdHower 1 1 10. Endo-6-n1tro-1,2,3,fl tetrahydro 1,4 methanopheny1ene naphthalene 2,3-d carboximide.

2' Acompound f the f l 11. Endo-6-am1no-1,2,3,4-tetrahydro 1,4 methanonaphthalene 2,3-dicarboximide. R3 O & References Cited by the Examiner /l UNITED STATES PATENTS H2 2,753,356 7/56 Laucius et a1. 260-326 2,813,877 11/57 Lambrech 260-326 3,053,731 9/62 Osterberg et al 16752 0 3,085,932 4/63 Rubin 16752 0 in which 1 is lower alkyl, and each group 2 and e is 4 NICHOLAS s. RIZZO, Primary Examiner.

hydrogen.

3. A compound of the formula JULIAN LEVITT Exammer' 

1. A MEMBER OF THE GROUP CONSISTING OF A COMPOUND OF THE FORMULA 